A Phase 2, Open-Label, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of Intracerebroventricular BMN 190 in Pediatric Patients < 18 Years of Age With CLN2 Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 14
- 试验地点
- 4
- 主要终点
- Motor Language (ML) Scale: Rate of Decline in the 0 to 6-point ML Score.
研究概览
简要总结
This Phase 2 open-label, multicenter study will evaluate the safety, tolerability, and efficacy of BMN 190 intracerebroventricular (ICV) administration every other week (qow) for a period of 144 weeks, in patients with CLN2. The study is designed to assess disease progression in CLN2 patients treated with BMN 190 compared to natural history data from untreated historical controls.
详细描述
BMN 190 is a recombinant form of human tripeptidyl peptidase 1 (TPP1), the enzyme deficient in patients with CLN2 diseases (also known as classical late-infantile CLN2, cLINCL, or Jansky-Bielschowsky disease), a form of Batten Disease. As an enzyme replacement therapy (ERT), BMN 190 is designed to help restore TPP1 enzyme activity. BMN 190 is designed to reduce the progressive, pathologic accumulation of lysosomal storage material. 190-203 is a Phase 2 open-label, multicenter study that will evaluate the safety, tolerability, and efficacy of BMN 190 in pediatric patients < 18 years of age with CLN2 disease. Study drug dosing will be determined by the patient's age and administered via intracerebroventricular (ICV) infusion every other week (qow), for a duration of 144 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of CLN2 disease as determined by TPP1 enzyme activity (dried blood spot) in the fibroblasts and leukocytes available at Screening
- •Quantitative clinical assessment of the Hamburg motor-language aggregate score 3-6 at Screening on CLN2 disease motor-language scale, as defined in the Ratings Assessment Guideline
- •< 18 years of age at the time of informed consent
- •Written informed consent from parent or legal guardian and assent form subject, if appropriate
- •Males and females who are of reproductive age should practice true abstinence, defined as no sexual activity, during the study and for 6 months after the study has been completed (or withdrawal from the study). If sexually active and not practicing true abstinence, males and females of reproductive age must use a highly effective method of contraception while participating in the study.
- •Ability to comply with protocol required assessments (ICV implantation, drug administration, laboratory sample collection, electroencephalogram (EEG), electrocardiogram (ECG),magnetic resonance imaging (MRI), etc.)
排除标准
- •Presence of another inherited neurological disease, e.g., other forms of CLN or seizures unrelated to CLN2 disease (patients with febrile seizures may be eligible)
- •Presence of another neurological illness that may have caused cognitive decline (e.g., trauma, meningitis, hemorrhage) or interference with disease rating (autism) before Screening
- •Presence of percutaneous feeding tube placement prior to enrollment
- •Has received stem cell, gene therapy, or ERT
- •Presence of contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory impairment, or clotting abnormalities)
- •Presence of contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain)
- •Episode of generalized motor status epilepticus within 4 weeks before the First Dose visit
- •Severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before the First Dose visit (enrollment may be postponed)
- •Presence of ventricular abnormality (hydrocephalus, malformation)
- •Presence of ventricular shunt
- •Has known hypersensitivity to any of the components of BMN 190
- •Has received any investigational mediation within 30 days before the first infusion of study drug or is scheduled to receive any investigational drug other than BMN 190 during the course of the study
- •Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's well being, safety, or clinical interpretability
- •Pregnancy any time during the study; a female subject judged by the investigator to be of childbearing potential will be tested for pregnancy
研究组 & 干预措施
BMN 190 recombinant human tripeptidyl peptidase-1 (rhTPP1)
An age-appropriate dose of BMN 190 administered via intracerebroventricular (ICV) infusion every other week (qow) for a duration of 144 weeks.
干预措施: BMN 190 recombinant human tripeptidyl peptidase-1 (rhTPP1) (Biological)
BMN 190 recombinant human tripeptidyl peptidase-1 (rhTPP1)
An age-appropriate dose of BMN 190 administered via intracerebroventricular (ICV) infusion every other week (qow) for a duration of 144 weeks.
干预措施: Intracerebroventricular access device (Device)
结局指标
主要结局
Motor Language (ML) Scale: Rate of Decline in the 0 to 6-point ML Score.
时间窗: Baseline to Last assessment (Week 169)
Rate of decline in 0 to 6-point ML score, \& primary analysis was based on up to 3-1 matching of Study 190-901 evaluable participants with Study 190-203 ITT participants. Rate of decline =(-1)x(48x7)x(Ending score - Starting score)/(Ending date - Starting date) A positive rate of decline means that subject declined, a negative rate of decline means that subject improved. The combined motor/gait and language (ML) score, as derived from Hamburg CLN2 rating scale, immediately preceding first infusion. The combined ML score is determined as sum of 0-3 point motor(M) \& language(L) subscales where 0 represents no function, \& 3 represents normal function, \& can range from 0(severely impaired) to 6(normal). Thus,high scores describe better function \& low scores describe poor function. The starting assessment is baseline ML assessment \& ending assessment is last ML score \>0. Note for Study 190-901, baseline ML assessment is defined as assessment of matching to Study 190-203 subj.
Probability of Unreversed 2-Point Decline in Motor-language (ML) Score or Score of 0
时间窗: Baseline to Last assessment (Week 169)
An unreversed 2-point decline is any decline of 2 points or more that had not reversed to a 1-point decline (or better) at last recorded observation. An unreversed score of 0 is a decline to 0 that had not increased to a score \>0 at last recorded observation ML score decline is measured by motor \& language domains on CLN2 rating scale. Combined motor/gait \&language (ML) score, as derived from Hamburg CLN2 rating scale, immediately preceding first infusion. Combined ML score is determined as sum of the 0-3 point motor(M)\&language(L) where 0 represents no function, \& 3 represents normal function, \& can range from 0 (severely impaired) to 6 (normal). Thus, high scores describe better function \& low scores describe poor function Model includes data up to week 169. Estimates from the model are presented for Wks 49, 97 \& 145 No.analyzed is no.of subj out of overall no.of participants analyzed who have not been censored/had unreversed 2-point decline/score of 0 at given time points.
Probability of Decline of Unreversed Motor-language (ML) Score of 0
时间窗: Baseline to Last assessment (Week 169)
The combined motor/gait and language (ML) score, as derived from the Hamburg CLN2 rating scale, immediately preceding the first infusion. The combined ML score is determined as the sum of the 0-3 point motor (M) and language (L) subscales where 0 represents no function, and 3 represents normal function, and can range from 0 (severely impaired) to 6 (normal). Thus, high scores describe better function and low scores describe poor function. Model includes data up to week 169. Estimates from the model are presented for Weeks 49, 97 and 145. No.analyzed is no.of subj out of overall no.of participants analyzed who have not been censored/had unreversed decline/score of 0 at given time points
Rate of Decline in Individual Motor Domains
时间窗: Baseline to Last assessment (Week 169)
Rate of decline = (-1) x (48 x 7) x (Ending score - Starting score)/(Ending date - Starting date). A positive rate of decline means that the subject declined, a negative rate of decline means that the subject improved. The 0-3 point motor (M) subscales, as derived from the Hamburg CLN2 rating scale, where 0 represents no function, and 3 represents normal function. Thus, high scores describe better function, and low scores describe poor function.
Rate of Decline in Individual Language Domains
时间窗: Baseline to Last assessment (Week 169)
Rate of decline = (-1) x (48 x 7) x (Ending score - Starting score)/(Ending date - Starting date). A positive rate of decline means that the subject declined, a negative rate of decline means that the subject improved. The 0-3 point language (L) subscales, as derived from the Hamburg CLN2 rating scale, where 0 represents no function, and 3 represents normal function. Thus, high scores describe better function and low scores describe poor function. Patients with baseline score of 0 are excluded.
次要结局
- Probability of Decline of Disease Manifestation at Week 49 & 97(Baseline to Last assessment (Week 169))
- Percentage Change From Baseline to Last Assessment: Volume of Cerebrospinal Fluid (mL)(Baseline to Last assessment (Week 169))
- Probability of Decline of Disease Manifestation at Week 145(Baseline to Week 145)
- Change From Baseline in ML Scale Score(Baseline to Week 49, Week 97, Week 145, & Week 169)
- Changes From Baseline in MLV Scale Score(Baseline to Week 49, Week 97, Week 145, & Week 169)
- Changes From Baseline in the 0-12 Point MLVS Motor, Language, Vision, and Seizure Subscales (MLVS) Score.(Baseline to Week 49, Week 97, Week 145, & Week 169)
- Percentage Change From Baseline to Last Assessment: Volume of Total Cortical Gray Matter (mL)(Baseline to Last assessment (Week 169))
- Percentage Change From Baseline to Last Assessment: Volume of Total White Matter (mL)(Baseline to Last assessment (Week 169))
- Change From Baseline to Last Assessment: Whole Brain Apparent Diffusion Coefficient Value(Baseline to Last assessment (Week 169))